Reagent-Controlled Divergent Synthesis of 2-Amino-1,3-Benzoxazines and 2-Amino-1,3-Benzothiazines

Abstract

A reagent-controlled chemoselective process has been devised for the synthesis of 4H-1,3-benzoxazines and related biologically important heterocycles in high yields under mild conditions. These scaffolds could be efficiently constructed using two different chemoselective reactions that rely on the choice of reagents and reaction conditions. The treatment of various 2-amino-arylalkyl alcohols with isothiocyanates afforded thiourea intermediates, which were reacted in situ with molecular iodine in the presence of triethylamine to give 2-amino-4H-1,3-benzoxazines, whereas the corresponding 2-amino-4H-1,3-benzothiazines were obtained by the reaction of thiourea intermediates in the presence of T3P (a mild cyclodehydrating agent) and triethylamine as the base. The described protocol represents the first example for the synthesis of 4H-1,3-benzoxazines via the dehydrosulfurization method using molecular iodine as the reagent.

P(III)‐Mediated Cascade C‐N/C‐S Bond Formation: A Protocol towards the Synthesis of N,S‐Heterocycles and Spiro Compounds

“…In contrast, structurally enthralling 3‐thia‐1‐azaspiro compounds are barely explored, albeit their medicinal importance [7] . In continuation of our research in this area, [2f] here we have reported P(NMe 2 ) 3 ‐mediated annulation reactions of bis‐nucleophiles and isothiocyanates towards the preparation of diversified N , S ‐heterocycles (Scheme 1).…”

“…N ‐(8‐methyl‐4 H ‐benzo[ d ][1,3]thiazin‐2‐yl)benzamide ( 6 ca ) [2f] (Scheme 4): Off‐white solid ; R f =0.60 (SiO 2 , Hexane/EtOAc=8:2); purification system : CombiFlash MPLC (Hexane/EtOAc=80:20); yield : 251 mg (89%); m.p =128.0–129.2 °C (Lit [2f] 127–128 °C); 1 H NMR (400 MHz, DMSO‐ d 6 ) δ=11.59 (br, 1H), 8.02 (d, J =5.6 Hz, 2H), 7.59 (t, J =7.2 Hz, 1H), 7.49 (t, J =7.5 Hz, 2H), 7.17–7.14 (m, 1H), 7.05 (d, J =4.9 Hz, 2H), 3.93 (s, 2H), 2.31 (s, 3H) ppm; 13 C NMR (100 MHz, DMSO‐ d 6 ) δ=170.1 (less intense), 138.7 (less intense), 134.5 (less intense), 132.81, 129.97, 129.13, 128.79, 125.75, 124.98, 28.82, 17.74 ppm; MS (APCI): [M+1] + =283.1 (99.10%); HRMS (ESI‐QTOF, [M+H] + ): calculated for C 16 H 15 N 2 OS: 283.0905; found: 283.0902.…”

“…H 2 SO 4 [5c,e,8] . Our research group has recently reported the synthesis of benzothiazines by employing T3P (2,4,6‐tripropyl‐1,3,5,2,4,6‐trioxatriphosphorinane‐2,4,6‐trioxide)‐mediated cyclization of 2‐amino‐arylalkyl alcohols with isothiocyanates [2f] . Afar from these protocols, several other useful approaches towards the preparation of benzothiazine motifs are known [3e,9] .…”

A Facile Synthesis of 2-Aminobenzoxazines Based on Iodine­Catalyzed Desulfurative Cyclization

“…Benzoxazine and its derivatives are important scaffolds in biologically active molecules such as pharmaceuticals and agrochemicals (Figure 1). 1 Previous methods for the synthesis of the benzoxazines include the cyclization of thioureas mediated by 1,3-dicyclohexylcarbodiimide (DCC), 2 and starting from isothiocyanates, hypervalentiodine(III)-mediated desulfurative cyclization, 3 cyclization using 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) as a brominating reagent, 4 cyclodesulfurization with triphenylbismuth dichloride, 5 a Cu 2 O/TBAB-promoted approach in water, 6 and cyclization mediated by stoichiometric iodine in the presence of a base 7 (Scheme 1). However, these methods suffer from harsh reaction conditions, moderate yields, and the use of expensive and/or stoichiometric amounts of reagents.…”

Kinetic Resolution of Tertiary Benzyl Alcohols via Palladium/Chiral Norbornene Cooperative Catalysis

“…[9a] The reaction of 5 with 4nitrophenyl chloroformate and a following base treatment afforded benzoxazinone 7 in 90 % yield and 93 % ee. [22] Moreover, subjecting 5 to ethyl isothiocyanate then iodine provided benzofused heterocycle 8, [23] an analogue of the anticonvulsant drug etifoxine. It is worth mentioning that all these transformations proceeded without any erosion of the enantiopurity.…”